Packing and Electrostatic Effects on Folding and Binding

描述（由申请人提供）：这项工作的长期目标是发展和应用理论模型来分析蛋白质折叠和结合过程中形成的互补相互作用。分子以适当的亲和力和特异性识别彼此的能力是生物学和医学的核心。药物制剂的临床活性在很大程度上取决于其识别和干扰一个或少数分子靶标的能力；不良的副作用往往是由于缺乏对正确靶标的特异性而引起的。一个重要的研究领域包括理解天然蛋白质分子的设计原理，并开发工具来根据类似的原理设计修改或全新的分子。目前的建议侧重于(1)分子结构和结合伙伴的研究和工程方法的进一步发展，以及(2)特定生物分子的应用。现有算法在主干固定的情况下，能够有效地搜索侧链旋转空间；我们提出了新的方法来允许加入骨干自由度或对接自由度。我们以前已经开发了静电优化技术，允许计算理想的互补结合伙伴，其形状和电荷分布导致高亲和结合。我们建议扩展这些方法，以允许设计接近理想形状和电荷分布的实际配体分子。此外，虽然高亲和力或高稳定性一直是许多设计研究的重点，但我们也建议开发特异性工程方法。然后，我们将把这种方法应用于研究Arc抑制因子和信号转导中涉及磷酸盐识别的蛋白质，我们将与这些系统专家的实验学家合作，并将开展平行研究。

DESCRIPTION (provided by applicant): The broad long-term objectives of this work are to develop and apply theoretical models to analyze complementary interactions formed during protein folding and binding. The ability of molecules to recognize one another with appropriate affinity and specificity is central to biology and medicine. The clinical activity of pharmaceutical agents is due largely to their ability to recognize and interfere with one or a small number of molecular targets; undesirable side effects are frequently caused by lack of specificity for the correct target. An important area of research involves understanding the design principles of natural protein molecules and developing tools to engineer modified or entirely new molecules by similar principles. The current proposal focuses on (1) further developments in methodology for the study and engineering of molecular structures and binding partners and (2) applications to particular biological molecules of interest. Current algorithms efficiently search side chain rotameric space when the backbone is fixed; we propose new methods to allow incorporation of backbone degrees of freedom or docking degrees of freedom as well. We have previously developed electrostatic optimization techniques that allow computation of idealized complementary binding partners, whose shape and charge distribution lead to high affinity binding. We propose to extend these methods to allow the design of actual ligand molecules that approach the idealized shape and charge distribution. Moreover, while high affinity or stability has been the focus of many design studies, we propose to develop methods that engineer in specificity as well. We will then apply this approach to investigations of the well studied Arc repressor and of proteins involved in phosphate recognition in signal transduction, and we will collaborate with experimentalists who are experts in these systems and will carry out parallel studies.